Session 2: Cognitive and Social Phenotypes in Autism

Autism is a devastating disorder that impairs social interaction and communication, and is associated with repetitive stereotyped social behaviors. Autistic symptoms are first noted at ages where speech and complex social interaction are observable, and these symptoms generally continue throughout life. All persons with autism spectrum disorders have some disturbance of social behavior, suggesting that social interaction abnormalities are at the core of autism. Predisposition to develop autism is largely genetically determined. The mode of inheritance of autism is complex, and autism consists of a spectrum of disorders. Autism is likely to be due to multiple genes interacting in variable combinations by a variety of genetic mechanisms. Genes and chromosomal regions associated with imprinted or X-linked syndromes that include autism or autistic features have been identified. Although important, the relationship of these genes to more genetically complex forms of autism is not known.

An alternative to genetic studies of humans with autism or other neuropsychiatric disorders is to study animal models containing defined genetic mutations that display characteristics of these human disorders. Genetic factors are important modifiers of a variety of simple and complex behaviors in virtually all organisms. As in the human, genetic effects have been inferred from inbred strain analysis in rodents, or from linkage analysis in rodents and humans, but these studies have not yet resulted in the isolation of specific genes involved in behavioral modification. More recently, genes influencing specific behaviors have been identified by analyzing behavioral abnormalities in mice with targeted gene disruption. In many cases, unexpected behavioral defects were found in mice that were generated to evaluate the general functions of genes expressed in the central nervous system, often providing novel insights into processes that influence behavioral variation and aspects of human neuropsychiatric disorders. Such animal models are critically important to study in detail the effects of genetic mutations in the context of the whole organism and to understand pathways regulated by this gene. In addition, animal models can also be used to test therapies based on an understanding of these pathways.

When producing mice deficient for each of three mammalian Dishevelled genes, we unexpectedly found that Dvl1-deficient mice displayed a novel behavioral phenotype, including reduced social interaction and abnormalities of sensorimotor gating (Lijam et al. Cell 90:895, 1997). We hypothesize that the novel behavioral abnormalities displayed by Dvl1-deficient mice make them a potential genetic model for aspects of several human psychiatric disorders including autism. The relevance of the Dvl1-deficinet mouse human autism was underscored when mutations in human WNT2, a gene in the Dvl pathway, were identified from linkage studies and chromosomal abnormalities in autism at 7q31-33 (Wassink et al. Am. J. Medical Genet. Online May 2001). The novel behavioral abnormalities displayed by Dvl1-deficient mice make them a potential genetic model for aspects of several human psychiatric disorders including autism. The human WNT2 mutations found in autism and the phenotype of Dvl1-deficient mice suggest that the Wnt pathway is involved in social behavior in both humans and mice. These studies suggest that valuable information regarding complex human neuropsychiatric disorders such as autism can be gained by studying relevant mouse models.